Fanconi Anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by development abnormalities, bone marrow failure, and cellular hypersensitivity to DNA crosslinking agents. The systematic study of cell lines derived from FA patients has led to the cloning of eight FA genes (A, C, D1/BRCA2, D2, E, F, G, L) and the elucidation of a novel DNA repair pathway (the Fanconi Anemia/BRCA pathway). The elucidation of this pathway had broad significance for the understanding of the pathogenesis of aplastic anemia and cancer in the general population. The specific aims of this five year grant are to (i) identify the molecular sensor of the FA/BRCA pathway (ii) determine the structural elements of FANCD2 required for its functional interaction with BRCA2 in chromatin and required for its DNA repair activities, and (iii) evaluate the newly identified FA-I and FA-J complementation groups.